Anti-transglutaminase antibodies

Anti-transglutaminase antibodies (ATA) are antibodies found more frequently in certain autoimmune diseases. High levels (titers) of ATA are found in almost all instances of coeliac disease.^[1] Given the association of ATA with celiac disease, and the prevalence of coeliac disease it is estimated that ~1% of the population have potentially pathogenic levels of ATA.

ATA can be classified according to 2 different schemes. Transglutaminase isoform and the reactivity of immunoglobulin subclass (IgA, IgG) toward transglutaminases.

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Transglutaminase isoform reactivity

Anti-tissue transglutaminase

Antibodies to tissue transglutaminase (ATA or anti-tTG) are found in patients with coeliac disease. ATA are sometimes found in other autoimmune diseases, such as juvenile diabetes. ATA are involved in the destruction of the villous extracellular matrix and target the destruction of intestinal villous epithelial cells by killer cells. Deposits of anti-tTG in the intestinal epithelium predict coeliac disease.^[2]

anti-endomysial reactivity. The major pathogenic component of anti-endomysial antibodies (EMA) are ATA, and EMA compose most of ATA. EMA may represent antibodies that bind with higher affinity to cell-surface tTG.^[3] therefore targeting those cells for apoptosis. The antiendomysial antibody test is a histological assay for patient serum binding to esophageal tissue from primate.

Anti-epidermal transglutaminase

Antibodies to epidermal transglutaminase(eGT, also Keratinocyte transglutaminase) are the autoantibodies believed to cause dermatitis herpetiformis.

Immunoglobin subclass

ATA IgA are more frequently found in CD; however, ATA IgG are found in CD and at higher levels when affected individual had the IgA-less phenotype. The IgA-less phenotype is more common in CD than the normal population; however, one haplotype, DQ2.5 is found in most CD, has genetic linkage to the IgA-less gene location.

Associated Conditions

Viral associations. Frequent rotavirus infections in children with DR3-DQ2 serological haplotype create higher risk of coeliac disease (CD).^[4] A large fraction of CD patients have anti-tTG antibodies that also recognize arotavirus protein called VP7. These crossreactive antibodies stimulate monocyte proliferation. Rotavirus infection might explain some early steps in the autoimmune progression in CD.^[5] Rotavirus damage in the gut showed a type villous atrophy similar to advanced grades of CD.^[6] This suggests that viral proteins may take part in the initial flattening and could stimulate self-crossreactive anti-VP7 production. Antibodies to VP7 may also slow healing until the gliadin-mediated tTG presentation provides a continuous source of autoantibodies.

Juvenile diabetes and anti-tTG. Childhood (male) Type 1 diabetes (T1D) increases the risk for CD and vice versa^[7] and the early signs of CD may precede T1D in many cases.^[8] A search for CD in juvenile diabates patients revealed that GF diet resulted in some improvements.^[9] A elevated number of diabetes patients have ATA^[10] along with increased numbers of gluten-specific T-cells.

Rheumatoid arthritis. Studies of patients with rheumatoid arthritis showed highly increased frequencies of antibodies against guinea pig transglutaminase, human recombinant transglutaminase and peptidylarginine deiminase type 4 (PAD4). This suggests a potential for crossreactive antibodies between anti-tTG and anti-PAD4.^[11]

Asymptomatic ATA+. A recent screening^[12] of 7550 Briton's found 87 undetected ATA+. In this study a 50% increase of ATA was associated with:

• lower bone mineral density of the hip.
• lower hemoglobin levels
• decreased weight.
• lower cholesterol
• higher blood glucose

Similar studies

• increased mortality, particularly to cancer^[13]

Symptomatic ATA+

• greater impairment of neurophysiology (peripheral neuropathies and motor neuron disease.^[14]
• increased inflammatory bowel symptoms(not celiac or EMA).^[15]

Alcohol consumption. ATA correlated with biomarkers of alcohol consumption, proinflammatory cytokines and markers of fibrogenesis.^[16]

Mechanism of Autoimmunity

The antibodies to tissue transglutaminase follow a complex pathway of generation. For most antigens, T-cells specific to those antigens develop, for autoimmunity autoreactive T-cells are not suppressed or antigens escape the protective process. T-cells are stimulated by antigen, presented by MHC molecules (HLA in humans) and surface IgM on antigen reactive B-cells. These T-helper cells then stimulate B-cells to multiply and mature into plasma cells that make IgG to that protein.

For tTG autoimmunity (CD), T-cells are generated against wheat gliadin and similar gluten proteins of the trib Triticeae. The T-cells are defined by the ability to react to HLA-DQ8 and DQ2.5 restricted antigens and gliadin is one of the antigens. Gliadin is a favored dietary substrate for transglutaminase because of many enzyme reaction sites on gliadin. In disease, transglutaminase reacts with gliadin forming a linkage^[17]. In forming this bond transglutaminase becomes linked to T-cell epitopes on gliadin. B-cells with surface IgM that react to transglutaminase can present it with bound gliadin peptides to T-cells which stimulate B-cell maturation and proliferation to plasma cells making IgA or IgM.

ATA correlates with severity of CD. A recent study of children demonstrates that the level of ATA in correlates with the scalar Marsh score for the disease in the same patient.^[18]

ATA changes the behavior of tTG. Some studies have revealed that antibodies increase the activity of tTG, instead of inhibiting activity as is commonly encountered with function alterning antibodies. A recent study has shown that ATA also modify and increase replication in intestinal epithileal cells, by apparent interacting with cell-surface transglutaminase.^[19]

Genetics

Genetics of coeliac disease is the common genetic factor for ATA. However studies of children with coeliac disease reveals that patients with DR7 have higher titers to ATA ^[20]. The DR7 is commonly found with HLA-DR5-DQ7/DR7-DQ2 phenotype in celiac disease. DR7-DQ2 homozygotes are also found.

Links

Anti-Tissue Transglutaminase (tTG) Antibodies Also Found in Inflammatory Bowel Disease

References